The papillomaviruses are associated with naturally occurring cancers in humans. Over 60 different papillomaviruses (HPVs) have been identified. Approximately 18 of these have now been associated with genital tract lesions. The HPVs that affect the anogenital area can be separated on the basis of their clinical associations into two distinct groups. The first group, including HPV-6 and HPV-11, is generally associated with benign anogenital warts that infrequently progress to cancer and have been referred to as "low risk" viruses. The "high risk" group, including HPV-16 and HPV-18, is associated with lesions that are at high risk for malignant progression and with almost all cervical cancers. We have been studying the role that HPV may play in the progression of a benign lesion to a malignant lesion. In HPV-16 and HPV-18 associated human cancers, the viral genome is generally found to be integrated. Integration often occurs in the El or E2 open reading frame, such that it disrupts the expression of the E2 open reading frame. The E2 open reading frame of the papillomaviruses encodes a DNA binding protein which is involved in the regulation of viral promoters. Integration into the E2 ORF is believed to lead to the deregulation of the viral promoter upstream of the E6 and E7 open reading frames. The E6 and E7 ORFs of HPV-16 and HPV-18 have been shown to encode transforming proteins. Both the E6 and E7 gene products must be expressed for efficient immortalization of human keratinocytes. The E7 proteins of the genital tract HPVs have been shown to associate with the product of the retinoblastoma tumor susceptibility gene. The E6 protein of the "high risk" genital HPVs has been shown to complex with the p53 cellular protein, which is also believed to be a tumor suppressor gene.